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A NOVEL FORMULATION of HERBS with POTENT ANTI-AGEING ACTIVITY Mohit M

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A NOVEL FORMULATION of HERBS with POTENT ANTI-AGEING ACTIVITY Mohit M European Journal of Bioinformatics, Vol. 2:1-5, 2014 A NOVEL FORMULATION OF HERBS WITH POTENT ANTI-AGEING ACTIVITY Mohit M. Jaina, Nirmala Kumaria, Geeta Raib* aNEISS Wellness India Limited, Mumbai, India. bDepartment of Molecular and Human Genetics, Banaras Hindu University, Varanasi 221005, India. ABSTRACT Ageing is characterized by a progressive deterioration of physiological functions and metabolic processes. Sirtuin (SIRT1) is a NAD+-dependent protein deacetylase which is a human ortholog of the yeast SIR2 protein. The activation of SIRr2 affects wide variety of cellular processes ranging from metabolism, cell cycle, growth and differentiation, inflammation, senescence, apoptosis, stress response and ageing. There are natural anti- ageing drugs in the market like Resveraterol but some studies suggest that due to its interaction with contraceptive pills it should not be consumed by women taking them. Although, a diet rich in antioxidants seems to offer hope in delaying the onset of unhealthy disorders that accompany ageing, however no clinical treatment using natural herbs has yet been developed and natural anti-aging drugs are still unavailable. In the present study, we evaluated the binding of active ligands present in real grass with the SIRT1 and SIRT5 receptor and compared their binding energy and affinity with other reference anti-ageing drugs present in the market. A high throughput screening comprising of molecular docking, absorption, distribution, metabolism, excretion and toxicity predictions, logP values and percentage of human oral absorption value led to the identification of three potential compounds present in ‘Live Green Real Grass’ which could be considered for anti–ageing activity with better binding affinities than the reference drugs used. KEYWORDS : Anti-ageing, Reservetrol, SIRT, real grass ABBREVIATIONS : SIRT 1 / SIRT 5 - silent mating type information regulation 2 homolog 1 /5 FOXO - Forkhead-O-box NAD+ - Nicotinamide adenine dinucleotide INTRODUCTION towards healthy ageing, by modifying their lifestyle and adopting ways for prevention of diseases by In recent years owing to modernization, life healthy diet. style related disorders are on the rise at an exponential rate. Natural ageing depends greatly Many theories and mechanisms have been on diet and lifestyle. It is a fact that for those with proposed for premature ageing that can be healthier body aging is delayed compared to those targeted to slow down the ageing process. Five who lead a life of frequent smoking, alcohol major theories of ageing are: consumption, eating junk food and a sedentary i) Antioxidant/free radical theory, ii) lifestyle (Guarente et al., 2009). Lifestyle effects are Mitochondrial mutation theory, iii) Cell debris/ controlled by proteins called sirtuins, which keep cleansing theory, iv) Hormonal changes, and v) cells live and healthy, even in stress, by regulating Calorie restriction theory. According to the free many hormones and their networks, regulatory radical theory (Harman, 1992), free radicals proteins and other genes (Guarente et al., 2009). produced during metabolic processes cause Today, several health issues resulting from poor degeneration of cells contributing towards diet and lifestyle as well as early symptoms of ageing. ageing are seen in people as early as in their 20’s. According to McLean et al., 2004, the primary Mitochondrial theory of aging states that causes of early ageing are stress, exposure to ageing in humans and animals is primarily due to harmful chemicals, pollutants, etc. Due to the accumulation of damages caused to the increased awareness people are now shifting mitochondria and mitochondrial DNA (Wei et al., 1 European Journal of Bioinformatics, Vol. 2:1-5, 2014 2001). stress, enhances the energy level thereby reduces premature ageing. Cuervo, 2008 in her cleansing theory states that as we age, lysosomes increasingly fail to perform Schuetz et al., 2007 states that SIRT5 is a NAD+ cleansing of the cells, leading to cell death and this dependent deacetylase, localized in mitochondrial leads to premature ageing.Vanja et al., 2010 in his matrix and activation of it is known to deacetylate hormonal theory states that the changes that the mitochondrial enzyme carbomoyl phosphate occur in the body because of the hormonal system synthetase 1 (CPSl), cytochrome C and a protein of are one of the very crucial reasons of ageing. As the mitochondrial inter-membrane space with a per calorie restriction theory proposed by McCay central function in oxidative metabolism (Schlicker et al., (1989), one should reduce the calorie et al., 2008). Therefore, these molecules can be consumption to increase in longevity. Sirtuin targeted to slow down the process of early or enzymes form a closed family of Nictotinamide premature ageing.The current study aims to adenine dinucleotide (NAD)-dependent examine the phytocompounds from a dietary deacetylases and ADP-ribosyltransferases, which is supplement, ‘Live Green Real Grass’ with anti- a life-span regulator in lower organisms. Chen et ageing and anti-oxidant properties for their al., (2005) and Haigis et al., (2010) state that there efficiency against anti-ageing targets (SIRT1 and are several genes in the sirtuin class, which SIRT5).The list of the phyto-nutrients identified is includes SIRT1, SIRT3, and SIRT4 that produce included in Table 1. enzymes which increase the activity of the mitochondria and slow down the cell's process of MATERIALS & METHODS ageing. As stated by Li et al., (2008) and Nakagawa 2.1 Active structure retrieval et al., (2009) Sirtuins proteins (SIRT1-7) regulate biological pathways, including energy metabolism The structures of active compounds of the (Li et al., 2008 and Nakagawa et al., 2009). botanicals used in the composition of the product Live Green Real Grass were acquired from As mitochondria is a key player in metabolism, PubChem(http://pubchem.ncbi.nlm.nih.gov) energy maintenance, and apoptosis, disruption of (Figure 1). mitochondrial pathways can lead to metabolic disease, oxidative damage, and cancer. Restoration 2.2 Preparation of receptor of these mitochondrial pathways may help in SIRT1 protein structure was downloaded from treating or preventing metabolic diseases, Protein Data Bank (PDB) with PDB ID - 4FZ3. The oxidative damage, and cancer. Therefore, Sirt1 and resolution factor of this structure was 2.10 Å and Sirt5 receptor present in mitochondria can be the method of incorporation was X-ray diffraction. targeted to slow down the process of early or PDB file of NAD-dependent protein deacylase premature ageing. sirtuin-1, receptor (PDB ID: 4FZA) has 2 chains. Sirtuins proteins (SIRT1-7) regulate various Chain A (NAD-dependent protein deacetylase biological pathways that are directly linked to anti– sirtuin-3, mitochondrial) contains 283 amino acid ageing such as ATP generation, metabolism, calorie residues and Chain B (Fluor-de-Lys peptide) restriction, autophagy and apoptosis. As stated by contains 6 amino acid residues. The proteins were Hirschey et al., (2010) SIRT1, SIRT6, and SIRT7 are preprocessed separately by deleting the substrate nuclear proteins, SIRT2 is found primarily in cofactor as well as the crystallographically cytosol, and SIRT3, SIRT4, and SIRT5 are observed water molecules (water without H mitochondrial proteins (Hirschey et al., 2010). bonds), correcting the mistakes in PDB file and SIRT1 interact with FOXO family of transcription optimizing hydrogen bonds. factors thereby deacetylates these transcription The protein SIRT5 was downloaded from factors (Brunet et al., 2004; Motta et al., 2004). Protein Data Bank with PDB ID - 4HD with a Further it regulates various processes like lipid resolution factor of 2.60 Å and the method of metabolism, stress resistance, and apoptosis (Gross incorporation being, X-ray diffraction. PDB file of et al., 2008) and enhances autophagy (Hariharan NAD-dependent protein deacylase sirtuin-5, et al., 2010). It was observed by Brunet et al., mitochondrial receptor (PDB ID: 3HDA) has 2 (2004) Deacetylation of FOXO3 by SIRT1 not only chains. Chain A (NAD-dependent protein deacylase inhibits its activity on apoptosis-related gene sirtuin-5, mitochondrial) contains 275 amino acid expression but drives its actions toward the residues and Chain F (Fluor-de-Lys peptide) induction of oxidative stress resistance genes contains 4 amino acid residues. The proteins were (Brunet et al., 2004). This is in line with the preprocessed separately by deleting the substrate hypothesis that activation of SIRT1 may allow the cofactor as well as the crystallographically cell to manage with high stress level/oxidative 2 European Journal of Bioinformatics, Vol. 2:1-5, 2014 observed water molecules (water without H We used resveratrol as our reference drug bonds), correcting the mistakes in PDB file, and which is a small polyphenolic compound which act optimizing hydrogen bonds. as potent natural anti-ageing agent. De la Lastra et al., 2005 reported resveratrol to be an activator of 2.3 Compounds used for study the sirtuin family of protein deacetylases. In this In this study we used the active compounds of study we have evaluated the mode of interaction the cereal grasses used in the composition of the of active ingredients of Live Green Real Grass with product Real Grass. The main active ingredients in the SIRT receptors. We used two docking methods, Real Grass are Abcissic acid, Chlorophyll, Moldock and Hex for evaluation of interaction of Spinasterol, stigmasterol, Beta-sitosterol and
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